Optic nerve diseases are common causes of irreversible blindness. Most are incurable or result in permanent visual loss by the time of diagnosis. An exception is glaucoma, the most common optic neuropathy, where the most important risk factor is elevated intraocular pressure. Treatments for glaucoma, currently limited to drugs or surgery to lower intraocular pressure, are often ineffective. Virtually all other optic neuropathies have no effective treatment, including ischemic optic neuropathy (the most common acute optic neuropathy of the elderly), optic neuritis (the most common acute optic neuropathy of the young), and many others. Loss of vision in optic neuropathies is caused by the selective death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain via their axons in the optic nerve. Nearly all optic neuropathies have in common an initial injury to RGC axons, which triggers the death of these neurons. Because RGCs are central nervous system neurons, their loss is irreversible in higher organisms. The overall goal of this proposal is to find innovative ways to prevent or delay visual loss from optic nerve disease by focusing on a novel family of synthetic molecules that regulate intracellular levels of reactive oxygen species (ROS). We have recently demonstrated that these molecules directly interfere with RGC death after axotomy. Specifically, we plan to: 1. Produce protected phosphine derivatives modified to cross cell membranes, act as prodrugs, and target RGCs. 2. Use in vitro and in vivo bioassays to identify lead neuroprotective compounds, including axotomy- induced RGC death in culture, RGC death induced by optic nerve crush in vivo, and ocular hypertension-induced RGC death. The proposed studies will take advantage of a multidisciplinary collaborative team, with Pi's expertise in acute optic neuropathies and the signaling of RGC death, co-investigator Di Polo's expertise in RGC survival signaling and the Morrison glaucoma model, and collaborator Raines's expertise in synthesizing the specific molecules relevant to this project. Our long-term goal is to identify novel pharmacological strategies to protect the optic nerve in culture and pre-clinical animal models, with the hope of identifying lead compounds that could lead to clinical trials for otherwise untreatable ootic neuropathies.